A PTP4A3 inhibitor for SARS-CoV-2-mediated acute lung injury

严重急性呼吸系统综合征冠状病毒（SARS-CoV-2）是目前 2019冠状病毒病疫情。与其他冠状病毒一样，SAR-CoV-2感染人类气道，并通过其S （刺突）蛋白，与人血管紧张素转换酶2（ACE 2）结合，并由宿主引发 丝氨酸蛋白酶TMPRSS 2。ACE 2和TMPRSS 2在肺微血管中均有表达。 上皮和内皮。一部分COVID-19患者出现急性呼吸窘迫综合征 （ARDS）和随后的败血性休克和多器官衰竭;大约一半会死亡。临床恶化， COVID-19的后期阶段被认为是由刺突蛋白结合到肺微血管引起的 内皮和上皮细胞，这导致呼吸道受损，最终导致全身性炎症 反应或细胞因子风暴。目前还没有FDA批准的治疗肺部感染的药物/治疗剂。 与COVID-19相关的损伤和ARDS。KeViRx计划开发一种全新的治疗药物 预防或减轻初始肺损伤并阻止致命细胞因子风暴的策略。 我们的先导化合物KVX-053是一种可逆的、选择性的、变构的PTP 4A 3磷酸酶抑制剂， 优异的体内药代动力学性质和药物样性质。此外，小鼠耐受多种 暴露于KVX-053在培养物中，KVX-053对人卵巢上皮细胞或成纤维细胞没有细胞毒性， 浓度高达25 µM。令人惊讶的是，我们发现KVX-053显著增强了肺内 细菌脂多糖致血管损伤前后微血管屏障功能的变化 内皮生长因子已知PTP 4A 3磷酸酶在SARS-CoV后12小时在肺细胞中被诱导 感染和控制细胞因子释放。第一阶段SBIR应用的总体假设是， PTP 4A磷酸酶家族在ARDS的急性肺损伤和全身炎症反应中起着重要的前哨作用。 该项目的总体目标是将KVX-053重新用于对抗SARS-CoV-2 感染和未来涉及急性肺损伤的病毒大流行。第一阶段SBIR应用程序有三个证明- 具体任务的概念。具体任务1将确定一种新的、有效的、变构的小分子的能力， PTP 4A抑制剂KVX-053阻断SARS-CoV-2 Spike 1蛋白介导的肺内皮屏障丧失 功能和细胞因子释放。具体任务2将确定KVX-053阻断SARS-CoV的能力， 2 Spike 1蛋白介导的肺泡上皮细胞屏障功能和细胞因子释放的体外研究具体 任务3将确定KVX-053抑制由SARS-CoV-2 Spike引起的小鼠急性肺损伤的能力 1蛋白质。

The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SAR-CoV-2, like other coronaviruses, infects human airways and enters cells via its S (Spike) protein, which binds to the human angiotensin-converting enzyme 2 (ACE2) and is primed by the host serine protease TMPRSS2. Both ACE2 and TMPRSS2 have been observed on pulmonary microvascular epithelium and endothelium. A subset of COVID-19 patients develop acute respiratory distress syndrome (ARDS) and subsequently septic shock and multi-organ failure; about half will die. The clinical worsening in the later phases of COVID-19 are thought to result from Spike protein binding to the pulmonary microvascular endothelium and epithelium, which leads to a damaged respiratory tract and ultimately a systemic inflammatory response or cytokine storm. There are currently no FDA-approved drugs/therapeutics that treat the pulmonary damage and ARDS associated with COVID-19. KeViRx is proposing to develop an entirely new therapeutic strategy that prevents or mitigates the initial pulmonary damage and halts the lethal cytokine storm. Our lead compound, KVX-053, is a reversible, selective, allosteric inhibitor of PTP4A3 phosphatase with excellent in vivo pharmacokinetic properties and drug-like properties. Moreover, mice tolerated multiple exposures to KVX-053. In culture KVX-053 was not cytotoxic to human ovarian epithelial cells or fibroblasts at concentrations up to 25 µM. Surprisingly, we found that KVX-053 markedly enhanced the pulmonary microvascular barrier function before and after injury caused by bacterial lipopolysaccharide and vascular endothelial growth factor. PTP4A3 phosphatase is known to be induced in lung cells 12 h after SARS-CoV infection and to control cytokine release. The overall hypothesis of this Phase I SBIR application is that the PTP4A phosphatase family has a sentinel role in the acute lung injury of ARDS and the systemic inflammatory response in COVID-19.The overall goal of the project is to repurpose KVX-053 for use against SARS-CoV-2 infection and for future viral pandemics involving acute lung injury. This Phase I SBIR application has three proof- of-concept Specific Tasks. Specific Task 1 will determine the ability of a novel, potent, allosteric, small molecule PTP4A inhibitor, KVX-053, to block SARS-CoV-2 Spike 1 protein-mediated loss of pulmonary endothelial barrier function and cytokine release in vitro. Specific Task 2 will determine the ability of KVX-053 to block SARS-CoV- 2 Spike 1 protein-mediated pulmonary alveolar epithelial barrier function and cytokine release in vitro. Specific Task 3 will determine the ability of KVX-053 to inhibit acute lung injury in mice caused by the SARS-CoV-2 Spike 1 protein.